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BRPI0408767A - inibidores de transcriptase reversa não-nucleosìdeos i para o tratamento de doenças mediadas pelo hiv - Google Patents

inibidores de transcriptase reversa não-nucleosìdeos i para o tratamento de doenças mediadas pelo hiv

Info

Publication number
BRPI0408767A
BRPI0408767A BRPI0408767-4A BRPI0408767A BRPI0408767A BR PI0408767 A BRPI0408767 A BR PI0408767A BR PI0408767 A BRPI0408767 A BR PI0408767A BR PI0408767 A BRPI0408767 A BR PI0408767A
Authority
BR
Brazil
Prior art keywords
hiv
treatment
reverse transcriptase
formula
compounds
Prior art date
Application number
BRPI0408767-4A
Other languages
English (en)
Inventor
James Patrick Dunn
Steven Swallow
Zachary Kevin Sweeney
Original Assignee
Hoffmann La Roche
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche
Priority to BR122016023941-1A priority Critical patent/BR122016023941B1/pt
Publication of BRPI0408767A publication Critical patent/BRPI0408767A/pt
Publication of BRPI0408767B1 publication Critical patent/BRPI0408767B1/pt
Publication of BRPI0408767B8 publication Critical patent/BRPI0408767B8/pt

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D271/00Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/101,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/1131,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41961,2,4-Triazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D249/00Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/081,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/101,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12Oxygen or sulfur atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D285/00Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01Five-membered rings
    • C07D285/02Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/121,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/1251,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/13Oxygen atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • AIDS & HIV (AREA)
  • Oncology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyridine Compounds (AREA)

Abstract

"INIBIDORES DA TRANSCRIPTASE REVERSA NãO-NUCLEOSìDEOS I PARA O TRATAMENTO DE DOENçAS MEDIADAS PELO HIV". A presente invenção refere-se a novos compostos heterocíclicos de fórmula (I), em que R¬ 1¬-R¬ 4¬, X¬ 1¬ e X¬ 2¬ são como definidos no sumário e sais e solvatos farmaceuticamente aceitáveis destes, métodos para inibir ou modular a transcriptase reversa do Vírus da Imunodeficiência Humana (HIV) com compostos de fórmula (I), composições farmacêuticas contendo a fórmula I misturadas com pelo menos um solvente, veículo ou excipiente e processos para se preparar os compostos de fórmula I. O compostos são úteis para o tratamento de distúrbios, em que o HIV e os vírus geneticamente relacionados estão envolvidos.
BRPI0408767A 2003-03-24 2004-03-22 inlbidores da transcriptase reversa não-nucleosídeos para tratamento de doenças mediadas pelo hiv, seu uso, e composição farmacêutica BRPI0408767B8 (pt)

Priority Applications (1)

Application Number Priority Date Filing Date Title
BR122016023941-1A BR122016023941B1 (pt) 2003-03-24 2004-03-22 Inibidores da transcriptase reversa não-nucleosídeos para tratamento de doenças mediadas pelo hiv, seu uso e composição farmacêutica

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US45713003P 2003-03-24 2003-03-24
US60/457,130 2003-03-24
PCT/EP2004/002995 WO2004085411A1 (en) 2003-03-24 2004-03-22 Non-nucleoside reverse transcriptase inhibitors i for treating hiv mediated diseases

Publications (3)

Publication Number Publication Date
BRPI0408767A true BRPI0408767A (pt) 2006-03-28
BRPI0408767B1 BRPI0408767B1 (pt) 2017-10-31
BRPI0408767B8 BRPI0408767B8 (pt) 2021-05-25

Family

ID=33098199

Family Applications (2)

Application Number Title Priority Date Filing Date
BRPI0408767A BRPI0408767B8 (pt) 2003-03-24 2004-03-22 inlbidores da transcriptase reversa não-nucleosídeos para tratamento de doenças mediadas pelo hiv, seu uso, e composição farmacêutica
BR122016023941-1A BR122016023941B1 (pt) 2003-03-24 2004-03-22 Inibidores da transcriptase reversa não-nucleosídeos para tratamento de doenças mediadas pelo hiv, seu uso e composição farmacêutica

Family Applications After (1)

Application Number Title Priority Date Filing Date
BR122016023941-1A BR122016023941B1 (pt) 2003-03-24 2004-03-22 Inibidores da transcriptase reversa não-nucleosídeos para tratamento de doenças mediadas pelo hiv, seu uso e composição farmacêutica

Country Status (20)

Country Link
US (2) US7208509B2 (pt)
EP (1) EP1608633B1 (pt)
JP (1) JP4708329B2 (pt)
KR (1) KR101122456B1 (pt)
CN (1) CN100588650C (pt)
AR (1) AR043673A1 (pt)
AU (1) AU2004224153B2 (pt)
BR (2) BRPI0408767B8 (pt)
CA (1) CA2518437C (pt)
CL (1) CL2004000590A1 (pt)
CO (1) CO5601029A2 (pt)
ES (1) ES2574580T3 (pt)
HR (1) HRP20050830A2 (pt)
IL (1) IL170343A (pt)
MX (1) MXPA05010210A (pt)
NO (1) NO334095B1 (pt)
NZ (1) NZ541829A (pt)
RU (1) RU2342367C2 (pt)
TW (1) TW200505441A (pt)
WO (1) WO2004085411A1 (pt)

Families Citing this family (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005097762A2 (en) * 2004-04-01 2005-10-20 Aventis Pharmaceuticals Inc. 1,3,4-oxadiazol-2-ones as ppar delta modulators
US8293778B2 (en) 2004-07-27 2012-10-23 Roche Palo Alto Llc Heterocyclic antiviral compounds
BRPI0513858B8 (pt) * 2004-07-27 2021-05-25 Hoffmann La Roche compostos de benziltriazolona como inibidores não-nucleosídeos da transcriptase reversa, seu processo de preparação, seu uso e composição farmacêutica que os compreende
EP1863777A1 (en) * 2005-03-24 2007-12-12 F.Hoffmann-La Roche Ag 1,2,4 -triazole-5-one compounds as heterocyclic reverse transcriptase inhibitors
AR057455A1 (es) 2005-07-22 2007-12-05 Merck & Co Inc Inhibidores de la transcriptasa reversa de vih y composicion farmaceutica
EP1937651B1 (en) * 2005-09-30 2008-12-24 F.Hoffmann-La Roche Ag Nnrt inhibitors
CA2625047A1 (en) 2005-10-19 2007-04-26 F. Hoffmann-La Roche Ag Phenyl-acetamide nnrt inhibitors
US20080293775A1 (en) * 2005-12-15 2008-11-27 Astrazeneca Ab Substituted Diphenylethers, -Amines, -Sulfides and -Methanes for the Treatment of Respiratory Disease
ME02258B (me) 2006-07-07 2015-12-31 Gilead Sciences Inc Modulatori farmakokinetičkih svojstava terapeutika
CL2007002105A1 (es) * 2006-07-21 2008-02-22 Hoffmann La Roche Compuestos derivados de 2-[3-(3-cianofenoxi)(fenoxi o fenilsulfanil)]-n-fenil acetamida, inhibidores de la transcriptasa inversa del vih; procedimiento de preparacion; composicion farmaceutica que comprende a dichos compuestos; y su uso para tratar u
WO2008019968A1 (en) 2006-08-16 2008-02-21 F. Hoffmann-La Roche Ag Non-nucleoside reverse transcriptase inhibitors
TW200831085A (en) * 2006-12-13 2008-08-01 Merck & Co Inc Non-nucleoside reverse transcriptase inhibitors
PL2487161T5 (pl) * 2007-02-23 2024-09-09 Gilead Sciences, Inc. <div>Modulatory właściwości farmakokinetycznych środków terapeutycznych</div><div> </div>
MX2009010932A (es) * 2007-04-09 2009-10-29 Hoffmann La Roche Inhibidores no nucleosidos de transcriptasa inversa.
AU2008257771B2 (en) 2007-05-30 2015-02-19 F. Hoffmann-La Roche Ag Non-nucleoside reverse transcriptase inhibitors
WO2008145563A2 (en) * 2007-05-30 2008-12-04 F. Hoffmann-La Roche Ag Process for preparing triazolones
WO2008157330A1 (en) * 2007-06-14 2008-12-24 Smithkline Beecham Corporation Chemical compounds
WO2008157273A1 (en) * 2007-06-14 2008-12-24 Smithkline Beecham Corporation Chemical compounds
JP2010530863A (ja) * 2007-06-22 2010-09-16 エフ.ホフマン−ラ ロシュ アーゲー 非ヌクレオシド逆転写酵素阻害剤としての尿素及びカルバマート誘導体
US8492415B2 (en) * 2007-07-03 2013-07-23 Yale University Azoles and related derivatives as non-nucleoside reverse transcriptase inhibitors (NNRTIs) in antiviral therapy (HIV)
EP2225239B1 (en) * 2007-12-21 2014-10-22 F. Hoffmann-La Roche AG Heterocyclic antiviral compounds
ME02181B (me) * 2010-03-30 2015-10-20 Merck Canada Inc Ne-nukleozidni inhibitori reverzne transkriptaze
CU23896B1 (es) * 2010-04-01 2013-05-31 Ct De Ingeniería Genética Y Biotecnología Método para inhibir la replicación del vih en células de mamíferos
JO3470B1 (ar) 2012-10-08 2020-07-05 Merck Sharp & Dohme مشتقات 5- فينوكسي-3h-بيريميدين-4-أون واستخدامها كمثبطات ناسخ عكسي ل hiv
CN104230929B (zh) * 2013-06-19 2015-11-18 华东师范大学 一种非核苷类hiv-1反转录酶抑制剂
LT3125894T (lt) 2014-04-01 2020-12-10 Merck Sharp & Dohme Corp. Živ atvirkštinės transkriptazės inhibitorių provaistai

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3274185A (en) 1963-10-08 1966-09-20 S E Massengill Company Phthalazine derivatives
US3813384A (en) 1972-01-17 1974-05-28 Asta Werke Ag Chem Fab Basically substituted benzyl phthalazone derivatives,acid salts thereof and process for the production thereof
PH24094A (en) 1986-12-19 1990-03-05 Merrell Dow Pharma 5-aryl-3h-1,2,4-triazol-3-ones and their use as anticonvulsants
US5436252A (en) 1986-12-19 1995-07-25 Merrell Dow Pharmaceuticals Inc. 5-aryl-3H-1,2,4-triazol-3-ones and their use in the treatment of neurodegenerative disorders
JP2593084B2 (ja) 1986-12-19 1997-03-19 メレルダウファーマスーティカルズ インコーポレーテッド 5−アリールー3h−1,2,4−トリアゾールー3−オン類の神経変性障害の処置への用途
US5103014A (en) 1987-09-30 1992-04-07 American Home Products Corporation Certain 3,3'-[[[(2-phenyl-4-thiazolyl)methoxy]phenyl]methylene]dithiobis-propanoic acid derivatives
US4826990A (en) 1987-09-30 1989-05-02 American Home Products Corporation 2-aryl substituted heterocyclic compounds as antiallergic and antiinflammatory agents
US4942236A (en) 1987-09-30 1990-07-17 American Home Products Corporation 2-aryl substituted pyridyl-containing phenyl sulfonamido compounds as antiallergic and antiinflammatory agents
US4966909A (en) 1989-12-20 1990-10-30 Merrell Dow Pharmaceuticals 4-benzyl-5-phenyl-2,4-dihydro-3H-1,2,4-triazol-3-ones and their use as anticonvulsants
US5331002A (en) 1990-04-19 1994-07-19 Merrell Dow Pharmaceuticals Inc. 5-aryl-4-alkyl-3H-1,2,4-triazole-3-thiones useful as memory enhancers
US5922751A (en) 1994-06-24 1999-07-13 Euro-Celtique, S.A. Aryl pyrazole compound for inhibiting phosphodiesterase IV and methods of using same
US5641796A (en) 1994-11-01 1997-06-24 Eli Lilly And Company Oral hypoglycemic agents
WO1997040017A2 (en) 1996-04-19 1997-10-30 Novo Nordisk A/S Modulators of molecules with phosphotyrosine recognition units
TW467902B (en) 1996-07-31 2001-12-11 Bristol Myers Squibb Co Diphenyl heterocycles as potassium channel modulators
NZ525138A (en) * 2000-10-30 2004-03-26 Kudos Pharm Ltd Phthalazinone derivatives for use as PARP inhibitors
UA82048C2 (uk) 2000-11-10 2008-03-11 Эли Лилли Энд Компани Агоністи альфа-рецепторів, активованих проліфератором пероксисом
JP2002275165A (ja) * 2001-01-12 2002-09-25 Sumitomo Pharmaceut Co Ltd トリアゾール誘導体

Also Published As

Publication number Publication date
BRPI0408767B1 (pt) 2017-10-31
NO20054264L (no) 2005-10-14
JP2006521319A (ja) 2006-09-21
US20040192704A1 (en) 2004-09-30
RU2342367C2 (ru) 2008-12-27
US7348345B2 (en) 2008-03-25
HRP20050830A2 (en) 2006-09-30
KR101122456B1 (ko) 2012-04-26
AR043673A1 (es) 2005-08-03
CO5601029A2 (es) 2006-01-31
IL170343A (en) 2014-03-31
NO20054264D0 (no) 2005-09-15
CA2518437C (en) 2012-07-10
CN1759104A (zh) 2006-04-12
TW200505441A (en) 2005-02-16
RU2005132632A (ru) 2006-06-10
EP1608633A1 (en) 2005-12-28
JP4708329B2 (ja) 2011-06-22
CA2518437A1 (en) 2004-10-07
EP1608633B1 (en) 2016-04-20
WO2004085411A1 (en) 2004-10-07
BR122016023941B1 (pt) 2021-10-13
KR20050115294A (ko) 2005-12-07
US7208509B2 (en) 2007-04-24
ES2574580T3 (es) 2016-06-20
AU2004224153B2 (en) 2009-04-02
NO334095B1 (no) 2013-12-09
AU2004224153A1 (en) 2004-10-07
MXPA05010210A (es) 2005-11-23
US20070179157A1 (en) 2007-08-02
NZ541829A (en) 2008-11-28
BRPI0408767B8 (pt) 2021-05-25
CL2004000590A1 (es) 2005-02-04
CN100588650C (zh) 2010-02-10

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Legal Events

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B06F Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]
B07D Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]
B07E Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]
B09A Decision: intention to grant [chapter 9.1 patent gazette]
B16A Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]
B16C Correction of notification of the grant [chapter 16.3 patent gazette]

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